Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs.

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune processes. Disulfiram eliminates the formation of N-gasdermin D (GSDMD) plasma membrane pores to prevent pyroptosis. Pyroptosis is a form of lytic cell death characterized by inflammasome activation and proinflammatory cytokine release that acts in the development of PH. We sought to investigate whether disulfiram could alleviate hypoxia-induced PH by inhibiting pyroptosis. METHODS: To investigate whether disulfiram alleviates the progression of pulmonary hypertension, rodents were exposed to chronic hypoxia (10% oxygen, 4 weeks) to induce PH. The severity of PH was assessed by measuring right ventricular systolic pressure, mean pulmonary artery pressure, and the degree of right ventricular hypertrophy. Western blotting was used to measure proteins associated with the pyroptosis pathway, and ELISA was performed to measure the secretion of IL-18 and IL-1ß, both of which are the primary methods for assessing pyroptosis. RESULTS: IL-18 and IL-1ß concentrations were higher in patients with PH than in normal controls. Disulfiram suppressed the progression of PH in mice and rats through the alleviation of pulmonary arterial remodelling. Pyroptosis-related proteins and the inflammasome were activated in rodent models of PH. Disulfiram inhibited the processing of GSDMD into N-GSDMD and attenuated the secretion of IL-1ß and IL18. In vivo experiments showed that disulfiram also inhibited lytic death in HPASMCs. CONCLUSIONS: Disulfiram treatment reduces PH progression through suppressing vascular remodelling by inhibiting GSDMD cleavage and pyroptosis. It might become a novel therapeutic option for the treatment of PH.